Autism is defined as a single disorder characterized by impairments in communication and social interaction and the presence of restricted or repetitive behaviors. The current diagnostic definition is based on behavioral characteristics, but there is mounting evidence that autism may represent a collection of overlapping neurodevelopmental disorders, resulting from a variety of neuroanatomical, neurophysiological, neuroimmunologic and/or genetic abnormalities. The wide range of possible etiologies and the heterogeneity of symptom expression among individuals with autism has caused speculation that there actually are several "autisms", i.e., clinical subtypes of the disorder that may have distinct causes, symptoms, comorbid conditions and treatments. The PDN research program aims to characterize the behavioral and biological manifestations of these subtypes of autism, and to examine the connection between the two, in an effort to identify unique etiologies and to develop more effective therapeutic and preventive interventions. During the reporting period, this project focused primarily on a longitudinal, phenotyping investigation of young children (ages 1-4 years) with autism. In addition, two new studies were designed and received approval from the NIMH scientific committee and the CNS Institutional Review Board. The goal of the first is stated in its title: "Identification of Characteristics Associated with Symptom Regression in Autism". This investigation will compare children with an early diagnosis of autism whose symptoms have remitted (partially or completed) with a cohort of children who received similar interventions (behavioral, pharmacological and biomedical) but did not receive significant benefits. It is hoped that specific predictors of response can be identified in the remitted group, which will lead to the development and application of more effective treatmens for the larger cohort of individuals with autism spectrum disorders. The study is actively recruiting children and adolescents with a history of remitted autism and their age-/sex-matched contrast groups. More information about the remitted autism study can be found at: http://clinicaltrials.gov/ct2/show/NCT00938054 The second recently approved study is not yet recruiting subjects, as an IND is pending which will permit the use of oxytocin and vasopressin as probes in a neuroimaging study of social cognition among young adults with autism spectrum disorders and age-/sex-matched healthy volunteers. This investigation utilizes functional magnetic resonance imaging (fMRI) to assess the impact of double-blind administration of oxytocin, vasopressin or placebo on behavior and brain function in response to tasks of social cognition. Comparisons across groups, tasks and drugs will be made to determine if individuals with autism have different patterns of brain activation than normal controls performing similar tasks of social cognition. The investigation will provide greater understanding of the nature of autism's social deficits and the activation patterns may provide important clues into the pathophysiology of the disorder, which in turn could lead to the development of novel therapeutic strategies. More information about the fMRI study will be forthcoming on ClinicalTrials.gov after the IND is secured. During the reporting period, recruitment was brisk for the primary study within this project. PDN staff screened more than one hundred children (ages 1 to 4 years) and enrolled 65 in the longitudinal, natural history study. It is expected that the study groups necessary for initial analyses will be filled over the next few months, as baseline evaluations will have been completed for 50 children with autism;50 children with autism and a history of developmental regression (developmental regression is defined by a significant loss of social and/or communication skills);50 typically developing healthy volunteers and 25-50 children with developmental delays but no symptoms of autism. At the baseline evaluations, the study participants receive comprehensive behavioral, neuropsychological, medical and neurological evaluations, as well as a routine and overnight electroencephalogram (EEG), neuroimaging with magnetic resonance imaging, modified polysomnography to evaluate sleep architecture, blood and urine samples (and children with autism receive a lumbar puncture to obtain cerebrospinal fluid for analysis), as well as assessments of environmental exposures, early medical history, genetics, genomics, and dysmorphology. Preliminary results from these evaluations have demonstrated genetic abnormalities in a small fraction of the children with autism, while more than half of the children have abnormalities of sleep architecture and/or the presence of abnormal, epileptiform discharges on routine and overnight EEG tracings. The latter findings led to the development of two targeted treatment trials - use of valproic acid to treat epileptiform discharges (currently under review) and use of donepezil to improve Rapid Eye Movement (REM) sleep (actively recruiting subjects;described in detail in Project MH002914-02: "Treatment of Medical Conditions among Individuals with Autism Spectrum Disorders" and at http://clinicaltrials.gov/ct2/show/NCT00695136 All children in the phenotyping study will be followed in the NIMH clinic for three years and will have annual evaluations that include behavioral assessments, clinical exams and laboratory studies. At the end of study participation, the comprehensive baseline evaluation will be repeated, including the laboratory assays, EEG, sleep study and MRI scans. Particular attention is being paid to the "N of 1 or 2" findings - unique physical, behavioral, genetic, neuroimaging or biochemical characteristics of children with autism that might provide clues to etiology or pathogenesis. The goal of the investigation is to determine if there are distinct groups of individuals within the spectrum of autistic disorders that share common profiles of biological and/or behavioral characteristics. Identification of such subgroups will provide new avenues for clinical and basic science research into the causes and treatments of autism. Interested parties are invited to learn more about the study at: http://clinicalstudies.info.nih.gov/detail/A_2006-M-0102.html